Prof. T.W. Robbins

BackgroundThe nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD.MethodsWe recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with …

One of the most complex human behaviours that defies singular explanatory models is suicidal behaviour, especially in the youth. A promising approach to make progress with this conundrum is to parse distinct subtypes of this behaviour. Utilizing 1,624 children with suicidal thoughts and behaviors (STBs) and 3,224 healthy controls from the ABCD Study, we clustered children with STB based on thirty-four cognitive and psychopathological measures which capture suicide-related risk-moderating traits. Environmental and genetic risk factors, as well as neuroanatomical characteristics of each subtype, were then compared with controls. We identified five distinct STB subtypes, each revealing unique neuroanatomy, environmental/genetic risks, and persistence patterns. Subtype 1 (Depressive, 9.6%) exhibited the most severe depressive symptoms. Subtype 2 (Externalizing, 20.1%) displayed anatomical and functional alterations in frontoparietal network and increased genetic risk for ADHD. Subtype 3 (Cognitive Deficit, 20.4%) demonstrated lower cognitive performance and widespread white-matter deficits. Subtype 4 (Mild Psychotic, 22.2%) presented higher prodromal psychotic symptoms, often unnoticed by parents. Subtype 5 (High Functioning, 27.6%) showed larger total brain volume, better cognition, and higher socio-economic status, contrasting subtypes 1-4. Only Subtypes 1 and 2 demonstrate persistent STB features at the 2-year follow-up. Our results suggested that youth suicidal behaviour may result from several distinct bio-behavioral pathways that are identifiable through co-occurring psychopathology, and provide insights into the …

2023-08-18 Assigned to SIRGARTAN HOLDINGS LTD reassignment SIRGARTAN HOLDINGS LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GARZYA, VICENZO, ROBBINS, Trevor, SIREAU, Nicolas Thierry, TANCOCK, Jon

Cognitive flexibility, the ability to adapt behavior in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Evidence suggests that flexibility, which can be operationalized using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behavior and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on cognitive flexibility and underlying RL mechanisms. Thirty-six male Lister-hooded rats were trained on the valence-probe visual discrimination (VPVD) task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning performance and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to VPVD choice data to extract RL parameters, including a novel model designed specifically for this task. 5-HT2AR antagonism impaired reversal learning during certain phases. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate at high and low doses. The low dose also increased exploration (beta) and increased stimulus and side stickiness (kappa). 5-HT2CR antagonism also increased beta, but …

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including substance use disorder and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesised to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%:20% basis, that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcbS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). Moreover, the exploitation-exploration parameter, beta, was increased (indicating greater exploitation of information) when this pathway was optogenetically stimulated after a spurious loss (i.e. an incorrect (20%) response at the 80% reinforrced location) compared to after a spurious win (i.e. a correct (20%) response at the 20% reinforced location). VTA -> NAcbS stimulation during other phases of the behavioural task was without effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or …

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive–compulsive disorder. However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning, using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition (‘stickiness’) or reinforcement learning rates following manipulations intended to increase or decrease serotonin function. More …

Compulsive behaviour, an apparently irrational perseveration in often maladaptive acts, is a potential transdiagnostic symptom of several neuropsychiatric disorders, including obsessive-compulsive disorder and addiction, and may reflect the severe manifestation of a dimensional trait termed compulsivity. In this Review, we examine the psychological basis of compulsions and compulsivity and their underlying neural circuitry using evidence from human neuroimaging and animal models. Several main elements of this circuitry are identified, focused on fronto-striatal systems implicated in goal-directed behaviour and habits. These systems include the orbitofrontal, prefrontal, anterior cingulate and insular cortices and their connections with the basal ganglia as well as sensoriomotor and parietal cortices and cerebellum. We also consider the implications for future classification of impulsive–compulsive disorders and …

BackgroundIndividuals with cocaine use disorder or gambling disorder demonstrate impairments in cognitive flexibility: the ability to adapt to changes in the environment. Flexibility is commonly assessed in a laboratory setting using probabilistic reversal learning, which involves reinforcement learning, the process by which feedback from the environment is used to adjust behavior.AimsIt is poorly understood whether impairments in flexibility differ between individuals with cocaine use and gambling disorders, and how this is instantiated by the brain. We applied computational modelling methods to gain a deeper mechanistic explanation of the latent processes underlying cognitive flexibility across two disorders of compulsivity.MethodWe present a re-analysis of probabilistic reversal data from individuals with either gambling disorder (n = 18) or cocaine use disorder (n = 20) and control participants (n = 18), using a …